Calcium phosphates (CaP) and in particular hydroxyapatite (Ca10(PO4)6(OH)2, HA), is a mineral that is widely used in medical applications due to its similarity to the mineral components of bone and teeth and its biocompatibility. Furthermore hydroxyapatite is non-toxic, biocompatible and bioactive. This means that hydroxyapatite is not harmful and not recognized as a foreign body and on the other hand that it may have positive effects on remodelling of bone. Hence hydroxyapatite has been widely used in bone repair and as drug/gene delivery vehicle, catalyst, ion adsorption/exchange agent, photoelectric regent, etc. Resorbable nanoparticles (i.e. particles that can be dissolved in vivo) are of special interest for a number of applications, e.g. bone void fillers, drug delivery vehicle, desensitization of dentin tubuli, etc.
Hydroxyapatite in bone is a multi-substituted calcium phosphate, including traces of CO32−, F−, Cl−, Mg2+, Sr2+, Si4+, Zn2+, Ba2+, Fe3+, etc. These ionic substitutions play an important role in bone formation and normal functions, such as the solubility, the crystal structure and the surface chemistry of the material.
Fluoride exists in bone and teeth of vertebrate bodies. It was reported that the substitution of fluoride for OH sites and formation of fluoride-substituted hydroxyapatite enhanced the acid resistance and the mechanical properties of hydroxyapatite bioceramics (Gross et al., Biomaterials 2004; 25:1375-1384), and induced better biological response (Robinson et al., Crit Rev Oral Biol Med 2000; 11:481-495).
Silicon has been found to be essential for normal bone and cartilage growth and development. Synthetic calcium phosphate that includes trace levels of Si in their structures demonstrate markedly increased biological performance in comparison to stoichiometric calcium phosphate (Pietak et al., Biomaterials 2007; 28:4023-4032). The improvement in biological performance can be attributed to Si-induced changes in the material properties and also to the direct effects of Si in physiological processes of the bone and connective tissue systems. Si substitution promotes biological activity by the transformation of the material surface to a biologically equivalent calcium phosphate by increasing the solubility of the material, by generating a more electronegative surface and by creating a finer microstructure. Release of Si complexes to the extracellular media and the presence of Si at the material surface may induce additional dose-dependent stimulatory effects on cells of the bone and cartilage tissue systems.
Because strontium is chemically and physically closely related to calcium, it is easily introduced as a natural substitution of calcium in calcium phosphate. Strontium has proved to have the effects of increasing bone formation and reducing bone resorption, leading to a gain in bone mass and improved bone mechanical properties in normal animals and humans. Sr substituted hydroxyapatite ceramics have exhibited better mechanical properties than pure hydroxyapatite, and enhanced the proliferation and differentiation of osteoblast cells in in vitro study (Landi et al., Acta Biomaterials 2007; 3:961-969). The positive effect of strontium-ions is used in a pharmaceutical, called strontium ranelate, which is applied to people with osteoporosis.
Methods to produce pure CaP particles, spherical granules and bulk materials have been described in the prior art and include wet chemical precipitation, sol-gel or hydrothermal synthesis, as described in e.g. U.S. Pat. Nos. 5,858,318, 7,326,464, 5,702,677 and Hui Gang Zhang, Qingshan Zhu, Yong Wang, Chem. Mater. 2005, 17, 5824-5830.
In other processes, the synthesis of calcium phosphate mimic biomineralization, which is a natural self-assembly process by which this kind of mineral is formed in living organisms. Moreover, synthesis of mineral nanomaterials with specific morphologies and structures from a solution attracts increasing attention because of their unique physical, chemical and biological properties and potential applications in advanced functional materials.
Current synthesis of mineral nanomaterials with different morphologies, such as spheres, fibers and rods, core-shell structures and mesoporous structures, mimicking a biomineralization process, are concentrated on self-assembly using surfactants and biomolecules (Xu et al, J Mater Chem 2007;17:415-449). For example, the nucleation and growth of calcium phosphate can be controlled by some specific surfactants or biomolecules that direct the growth and hence control the morphology of the grown nanomaterials. Without surfactants, the morphology is inherently controlled by the crystals preferentially growing on a specific crystal plane with lowest surface tension in the solution. For example, in a supersaturated solution (usually comprising calcium and phosphate ions) calcium phosphate spontaneously grows like flakes or fibers/rods, which are oriented along the crystals c axis.
Not all morphologies are convenient to serve as delivery particles, catalyst support, ion adsorption/exchange agent, etc., until now when for example rod, tubular, sheet or spherical shaped nanoparticles have been investigated. By way of example, to make a drug delivery process efficient, high surface areas and porous structures are advantageous to adsorb as much active substance as possible and, of course, there is as well the requirement of biocompatibility and a bond between carrier and substance.
One problem for the preparation of CaP particles is to control size distribution and shape of the particles. Often the size distribution is wide and caused by the hexagonal symmetry and the lattice parameters of CaP. Most likely an orientation along the c-axis and therewith a pin-like shape occurs.